Inhibition of 2-arachydonoylgycerol degradation attenuates orofacial neuropathic pain in trigeminal nerve-injured mice
Inhibition of 2-arachydonoylgycerol degradation attenuates orofacial neuropathic pain in trigeminal nerve-injured mice
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DOI：
10.2334/josnusd.17-0005
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发表时间：
2018-03-01
影响因子：
1.9
通讯作者：
Kitagawa, Junichi
中科院分区：
文献类型：
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作者：
Kamimura, Rantaro;Hossain, Mohammad Z.;Kitagawa, Junichi
目前的治疗方法对口面部神经性疼痛无效，需要更好的选择。本研究采用下眶神经（ION）损伤小鼠，研究抑制单酰基甘油脂肪酶（MAGL）对口面神经病变疼痛的影响。单酰基甘油脂肪酶是一种降解内源性大麻素2-arachydonoylgycerol （2-AG）的酶。离子损伤后第3、5和7天，须垫机械刺激的头退缩阈值降低。在离子损伤后第7天注射选择性MAGL抑制剂JZL184，可在给药后2 h减弱头停阈值的降低。此外，离子损伤小鼠三叉神经尾侧亚核（Vc）和上颈脊髓（C1-C2）的magl免疫反应神经元数量明显高于假手术小鼠，但给药JZL184后减少。MAGL免疫反应性的增加表明，2-AG产量的增加伴随着2-AG的快速酶降解。JZL184抑制了这种降解，从而增加了大脑中2-AG的浓度，特别是在Vc和Cl-C2区域，从而减轻了疼痛。我们的研究结果表明，通过MAGL抑制剂抑制2-AG的降解是治疗口面部神经性疼痛的一种有希望的治疗选择。
Current therapeutics are not effective for orofacial neuropathic pain, and better options are needed. The present study used inferior orbital nerve (ION)-injured mice to investigate the effect of inhibiting monoacylglycerol lipase (MAGL), an enzyme that degrades the major endocannabinoid 2-arachydonoylgycerol (2-AG) in orofacial neuropathic pain. The head-withdrawal threshold to mechanical stimulation of the whisker pad was reduced on days 3, 5, and 7 after ION injury. Injection of JZL184, a selective inhibitor of MAGL, on day 7 after ION injury attenuated the reduction in head-withdrawal threshold at 2 h after administration. Moreover, the numbers of MAGL-immunoreactive neurons in the trigeminal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2) were significantly greater in ION-injured mice than in sham-operated mice but were reduced after administration of JZL184. The increase in MAGL immunoreactivity suggests that increased 2-AG production is followed by rapid enzymatic degradation of 2-AG. JZL184 inhibited this degradation and thus increased 2-AG concentration in the brain, particularly in the Vc and Cl-C2 regions, thus attenuating pain. Our findings suggest that inhibition of 2-AG degradation by MAGL inhibitors is a promising therapeutic option for treatment of orofacial neuropathic pain.